A common problem associated with drugs intended for parenteral, and especially intravenous, administration has been the solubilization of a slightly soluble or water-insoluble active ingredient (Sweetana et al., PDA J. Pharm. Sci. & Tech., 50, 330 (1995)). As a result, many drugs of potential benefit in cancer chemotherapy and other areas of therapeutics have been abandoned. Methods have been developed whereby drugs can be enveloped in micelles and placed into aqueous solutions (Hawthorne et al., J. Neurooncol., 33, 53–58 (1997)). Likewise, cosolvents and complexing agents allow some drugs to be dissolved in water (Badwan et al., U.S. Pat. No. 5,646,131). The use of these reagents, however, can be complex and have negative attributes due to the additional reagent required to dissolve the active ingredient (Sweetana et al. (1995), supra). Prodrugs also have been developed by attaching groups, such as phosphates and other conjugates, to increase their solubility and enhance their performance (Schacter et al., Cancer Chemother. Pharmacol., 34, S58 (1994); Kingston et al., U.S. Pat. No. 5,278,324).
One water-insoluble drug of potential beneficial use in cancer therapy is geldanamycin. The drug is an ansamycin isolated from the broth of Streptomyces hygroscopicus var. geldanus (DeBoer et al., Antiobiot., 23, 442 (1970)). It has been found to exert its antiproliferating and anticancer activities by binding with the heat shock protein 90 (Hsp90) chaperone and, in turn, altering the translocation properties of the tumor suppressor protein p53 (Stebbins et al., Cell, 239 (1997); Sepehrnia et al., J. Biol. Chem., 271, 15,084 (1996); Dasgupta et al., Experimental Cell Research, 29, 237 (1997)). Despite its therapeutic potential as an anticancer agent, initial studies indicate that the bioavailability of geldanamycin must be enhanced and the toxicity associated with the natural product reduced before significant progress can be made with respect to the anticancer use of geldanamycin. Chemical modifications of geldanamcyin could potentially provide analogs with improved bioactivity and bioavailability. While derivatives of geldanamycin have been developed to enhance the cancer-fighting effects of the drug, the low solubility of such derivatives have required the use of emulsifying or suspending agents in order to obtain aqueous solutions. This has tended to reduce the bioavailability of the drug, and has thereby affected its utility as an anticancer agent.
The present invention addresses these problems by providing a method of producing water-soluble analogues of water-insoluble drugs and, in particular, by providing a water-soluble analogue of the anticancer drug geldanamycin. Due to its thiol ether linkage, the analogue is expected to exhibit superior bioavailability and stability under physiological conditions.